Bacterial-Induced Sepsis: A New Treatment Strategy

描述（由申请方提供）：脓毒症是一种常见的危及生命的医学疾病，其特征是发生失调的炎症免疫反应和相关的组织损伤。这种失调的炎症反应是通过响应细菌和/或细菌产物（例如LPS）激活Toll样受体（TLR）信号传导而引发的。目前的治疗是有限的，涉及使用抗生素来控制感染和支持措施，以帮助患者多器官功能衰竭。需要新的治疗策略来解决脓毒症患者中观察到的免疫反应失调，从而限制组织损伤并提高存活率。我们已经确定并表征了一种新的肽，称为P13，一种有效的但暂时的细胞内TLR信号传导抑制剂。在目前的II期SBIR资助下进行的研究已经i）证明了P13是施用低剂量和高剂量LPS的动物中体内血清炎症介质的有效抑制剂，ii）确立了P13在致死性高剂量LPS诱导的脓毒症模型中显著提高存活率的功效，iii）在临床相关的盲肠结扎和穿孔（CLP）多微生物脓毒症模型中确立了P13提高存活率的功效，以及iv）在初步实验中证明了P13的有利安全性特征。当在全身性炎症和疾病开始后给药时，与对照治疗动物的0%存活率相比，P13将这些模型中的存活率提高了30-50%。本次II期更新申请的主要目标是完成FDA批准该肽作为人类临床试验中的新治疗药物所需的所有临床前疗效和安全性测试。基于我们的研究显示P13在脓毒症临床前模型中改善生存率的疗效和证明有利安全性特征的数据，我们在本II期更新申请中提议进行FDA要求的所有必要研究，以将P13定位于人体临床试验。这些研究将包括在CLP模型中建立最佳P13治疗参数，并开发用于检测血清和组织中P13的灵敏测定法（具体目标1）。这些研究将支持FDA批准药物所要求的IND使能研究的适当P13给药和暴露参数。为了支持向FDA提交IND申请以获得P13的药物批准，将确定最佳临床治疗方案并确定与P13治疗相关的生物标志物（具体目标#2）。将对P13进行详细的IND使能研究，提供完整的非临床药理学、药代动力学和毒理学数据包（具体目标3）。在本II期更新申请结束时，将向FDA提交IND，以便在I期人体临床试验中使用P13。 公共卫生相关性：细菌性脓毒症是一种发病率和死亡率不断上升的疾病，需要新的治疗选择。我们已经确定了一种新的抗炎肽，已证明其在多微生物败血症动物模型中限制炎症和增加存活率的功效。我们目前的研究将完成FDA批准这种肽作为脓毒症新疗法启动人体临床试验所需的所有临床前和安全性测试。

DESCRIPTION (provided by applicant): Sepsis is a prevalent and life-threatening medical condition characterized by development of a dysregulated inflammatory immune response and associated tissue damage. This dysregulated inflammatory response is initiated by activation of Toll-Like receptor (TLR) signaling in response to bacteria and/or bacterial products, such as LPS. Current treatments are limited and involve the use of antibiotics to control infection and supportive measures to assist patients with multi-organ failure. New treatment strategies are needed to address the dysregulated immune response seen in patients with sepsis, thereby limiting tissue damage and enhancing survival rates. We have identified and characterized a novel peptide, termed P13, a potent yet temporary inhibitor of intracellular TLR signaling. Studies performed under the current Phase II SBIR grant have i) demonstrated that P13 is a potent inhibitor of in vivo serum inflammatory mediators in animals administered both low-dose and high-dose LPS, ii) established the efficacy of P13 to significantly enhance survival rates in a lethal high-dose LPS-induced model of sepsis, iii) established the efficacy of P13 to enhance survival rates in the clinically relevant cecal ligation and puncture (CLP) polymicrobial sepsis model, and iv) demonstrated in pilot experiments a favorable safety profile for P13. P13, when administered after initiation of systemic inflammation and disease, improved the survival rate in these models 30-50% as compared with 0% survival in control treated animals. The primary goal of this Phase II Renewal Application is to complete all pre-clinical efficacy and safety testing required by the FDA for approval of this peptide as a new therapeutic in human clinical trials. Based on our studies showing efficacy of P13 to improve survival rates in sepsis pre- clinical models and data demonstrating a favorable safety profile, we propose in this Phase II Renewal Application to conduct all necessary studies required by the FDA to position P13 for human clinical trials. These studies will include establishing optimal P13 treatment parameters in the CLP model and development of a sensitive assay for detection of P13 in serum and tissues (specific aim #1). These studies will support appropriate P13 dosing and exposure parameters for the IND-enabling studies required by the FDA for drug approval. In support of the IND filing to the FDA for drug approval of P13, an optimal clinical treatment protocol and identification of biologic markers associated with P13 treatment will be determined (specific aim #2). Detailed IND-enabling studies for P13, providing a complete non-clinical pharmacology, pharmacokinetic, and toxicology data package will be performed (specific aim #3). At the conclusion of this Phase II Renewal Application an IND will be filed with the FDA for use of P13 in a Phase I human clinical trial. PUBLIC HEALTH RELEVANCE: New treatment options are needed for patients with bacterial-induced sepsis, a disease with increasing morbidity and mortality. We have identified a novel anti-inflammatory peptide that has demonstrated efficacy to limit inflammation and increase survival rates in an animal model of polymicrobial sepsis. Our current studies will complete all pre-clinical and safety testing required for FDA approval of this peptide to initiate human clinical trials as a new treatment for sepsis.